Pharmaceutical compositions based on a scopineester and nicotinamide derivatives

Abstract

The present invention relates to novel pharmaceutical compositions based on a scopineester of formula 1 wherein X − has the meanings specified in the description and claims and one ore more, preferably one nicotinamide derivative, processes for preparing them and their use in the treatment of respiratory diseases.

1 ) a pharmaceutical composition comprising as active substances one or more anticholinergics of formula 1 
       
         
           
           
               
               
           
         
       
       wherein 
 X −  denotes an anion with a single negative charge, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate,  
 combined with one or more nicotinamide derivative (2), optionally in the form of the enantiomers, mixtures of the enantiomers or in the form of the racemates thereof, optionally in the form of the solvates or hydrates and optionally together with a pharmaceutically acceptable excipient:  
 
     
     
         2 ) The pharmaceutical composition according to  claim 1 , wherein the active substances 1 and 2 are present either together in a single formulation or in two separate formulations.  
     
     
         3 ) The pharmaceutical composition according to  claim 1 , wherein in the compounds of formula 1, X −  is a negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulphonate and methanesulphonate.  
     
     
         4 ) The pharmaceutical composition according to  claim 1 , wherein in the compounds of formula 1, X −  denotes bromide.  
     
     
         5 ) The pharmaceutical composition according to  claim 1 , wherein the active substance 2 is selected from the group consisting of: 
 2-(4-Fluoro-phenoxy)-N-{4-[(2-hydroxy-3-methyl-benzoyl amino)-methyl]-benzyl}-nicotinamide,    3-(3-{4-[(3-Hydroxy-benzoylamino)-methyl]-benzyl carbamoyl}-pyridin-2-yloxy)-benzoic acid ethyl ester,    2-(4-fluoro-phenoxy)-N-{4-[(6-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(5-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(3-hydroxy-4-methyl-benzoylamino)methyl]benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(3-hydroxy-benzoylamino)-methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(4-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-4-methyl-benzoylamino)methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(3-hydroxy-2-methyl-benzoylamino)methyl]-benzyl}nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-5-methyl-benzoylamino)methyl]-benzyl}nicotinamide,    5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide,    5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-acetylamino)methyl]-benzyl}nicotinamide,    5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(4-hydroxy-benzoylamino)methyl]-benzyl}nicotinamide,    3-(3-{4-[(3-hydroxy-benzoylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethyl ester,    3-(3-{4-[(2-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethyl ester,    3-(3-{4-[(3-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethyl ester,    3-(3-{4-[(4-hydroxy-phenacetylamino)methyl]-benzylcarbamoyl}-pyridin-2-yloxy)benzoic acid ethyl ester,    2-(3,4-Difluoro-phenoxy)-5-fluoro-N-[4-(2-hydroxy-5-methyl-benzoylamino)-cyclohexyl]-nicotinamide,    2-(3,4-Difluoro-phenoxy)-5-fluoro-N-[4-(2-hydroxy-5-hydroxymethyl-benzoylamino)-cyclohexyl]-nicotinamide,    2-(4-fluoro-phenoxy)-N-{4-(1-hydroxy-1-methyl-ethyl)-benzyl}nicotinamide,    (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid,    N-(R)-(9-Amino-4-oxo-7-phenyl-1,2,4,5-tetrahydro-azepino[3,2,1-hi]indol-5-yl)-nicotinamide,    N-(R)-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-1,4]diazepino[6,7,1-hi]-indol-3-yl)-nicotinamide,    N-(R)-(9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi]indol-3-yl)-isonicotinamide,    1H-Indole-2-carboxylic acid (4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3(R)-yl)-amide,    N-(R)-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi]indol-3-yl)-isonicotinamide,    N-(R)-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi]indol-3-yl)-3,5-dichloro-isonicotinamide,    N-(R)-(9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino [6,7,1-hi]indol-3-yl)-3,5-dichloro-isonicotinamide,    [4-(9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-ylcarbamoyl)-pyridin-3-(R)-yl]-carbamic acid tert-butyl ester,    4-Amino-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diaze-pino[6,7,1-hi]indol-3(R)-yl)-3,5-dichloro-benzamide,    4-Amino-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diaze-pino[6,7,1-hi]indol-3(R)-yl)-3,5-dichloro-benzamide,    9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[34-c]1,2,4-triazolo[4,3-□]pyridine,    3-(tert-butyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3-4-c]1,2,4-triazolo[4,3-□]pyridine,    4′-[[[2-[4-Fluorophenoxy]pyridine-3-carbonyl]-amino]-methyl]-biphenyl-3-carboxylic acid;    4′-[[[2-Benzo[1,3]dioxol-5-yloxy]-pyridine-3-carbonyl}-amino]-methyl]-biphenyl-3-carboxylic acid;    4′-[[[2-Benzo[1,3]dioxol-5-yloxy]-pyridine-3-carbonyl}-amino]-methyl]-3′-fluoro-biphenyl-3-carboxylic acid;    4′-[[[2-[3-Cyano-phenoxy]-pyridine-3-carbonyl}-amino]-methyl]-biphenyl-3′-fluoro-biphenyl-3-carboxylic acid;    [4′-(([2-(Benzo[2,1,3]thiadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-biphenyl-4-yloxy]-acetic acid;    [4′-({[2-(Benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-biphenyl-4-yloxy]-acetic acid;    [4′-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-biphenyl-4-yloxy]-acetic acid;    (±)-2-[4′-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}methyl)-2-fluoro-biphenyl-4-yloxy]-propionic acid;    (±)-2-(Benzo[1,3]dioxol-5-yloxy)-N-(2′-fluoro-4′ [1-(1H-tetrazol-5-yl)-ethoxy]-biphenyl-4-ylmethyl}-nicotinamide;    (±)-2-[4′-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3′-fluoro-biphenyl-2-yloxy]-propionic acid;    (±)-2-(Benzo[1,3]dioxol-5-yloxy)-N-(2′-fluoro-4′ [1-(5-methyl-4H-[1,2,4]triazol-3-yl)-ethoxy]-biphenyl-4-ylmethyl}-nicotinamide;    (±)-N-[4′-(1-Carbamoyl-ethoxy)-2′-fluoro-biphenyl-4-ylmethyl]-2-(3-cyano-phenoxy)-nicotinamide;    (±)-2-[2,3′-Difluoro-4′-({[2-(3-methoxy-phenoxy)-pyridine-3-carbonyl]-amino}-methylbiphenyl-4-yloxy]-propionic acid;    2-(Benzo[1,3]dioxol-5-yloxy)-N-(4′-carbamoylmethyl-3-fluoro-biphenyl-4-ylmethyl)-nicotinamide;    [4′-({[2-(3-Cyano-phenoxy)-3-carbonyl]-amino}-methyl)-3′-fluoro-biphenyl-4-yl]-acetic acid;    2-(Benzo[1,3]dioxol-5-yloxy)-N-(4′-[(2-cyano-benzoylamino)-methyl]-2′-fluoro-biphenyl-4-ylmethyl)-5-fluoro-nicotinamide;    Pyridine-2-carboxylic acid (3′-fluoro-4′-([2-(4-fluoro-phenoxy)-nicotinamide]-methyl}biphenyl-4-ylmethyl)-amide;    2-(Benzo[1,3]dioxol-5-yloxy)-N-{2′-fluoro-4′-[1-methyl-1-(1H-tetrazol-5-yl)-ethyl]-biphenyl-4-ylmethyl}-nicotinamide;    5-Fluoro-N-(3-Fluoro-4′-{[(5-methyl-4H-[1,2,4]triazole-3-carbonyl)-amino]-methylbiphenyl-4-ylmethyl)-2-(3-methoxy-phenoxy)-nicotinamide;    2-(Benzo[1,3]dioxol-5-yloxy)-N-{2′-fluoro-4′-[(2-methoxy-benzoylamino)-methyl]-biphenyl-4-ylmethyl}-nicotinamide;    N-[4′-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2′-fluoro-biphenyl-4-ylmethyl]-2-(4-fluoro-phenoxy)-nicotinamide;    N-(2′-Fluoro-4′-{[(3H-imidazole-4-carbonyl)-amino]-methyl}-biphenyl-4-ylmethyl)-2-(3-nitro-phenoxy)-nicotinamide;    (±)-3-[4′-({[2-(3-Chloro-4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino)-methyl)-2-fluoro-biphenyl-4-yloxy]-butyric acid;    2-[4′-({[2-Benzo[2,1,3]thiadiazol-5-yloxy)-pyridine3-carbonyl]-amino}-methyl)-2-fluorobiphenyl-4-yl]-2-methyl-propionic acid;    (±)-2-[4′-({[2-(Benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino]methyl)-2-fluoro-biphenyl-4-yloxy)-propionic acid;    (±)-2-[3′-Fluoro-4′-({[2-(2-methyl-2H-benzotriazol-5-yloxy)-pyridine-3-carbonylamino}-methyl)-biphenyl-4-yloxy]-propionic acid;    2-(3-Cyano-phenoxy)-N-{2′-fluoro-4′[(pyridin-2-ylmethyl)-carbamoylo]-biphenyl-ylmethyl}-nicotinamide;    2-(Benzo[1,3]dioxol-5-yloxy)-N-{2′-fluoro-4′-[(quinolin-2-ylmethyl)-carbamoyl]-biphenyl-4-ylmethyl}-nicotinamide;    5-Fluoro-2-(4-fluoro-phenoxy) N-[3-fluoro-3′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-nicotinamide;    N-{3-Fluoro-4′-[(1-hydroxy-pyridin-2-ylmethyl)-carbamoyl]-biphenyl-4-ylmethyl}-2-(3-methoxy-phenoxy)-nicotinamide;    (±)-N-[3-Fluoro-4′-(2-hydroxy-1,2-dimethyl-propoxy)-biphenyl-4-ylmethyl]-2-(4-fluoro-phenoxy)-nicotinamide;    N-[2′-Fluoro-4′-(1-hydroxy-1-methyl-ethyl)-biphenyl-4-ylmethyl]-2-(4-fluoro-phenoxy)-nicotinamide;    2-(3-Chloro-4-fluoro-phenoxy)-N-[4′-(pyridin-2-ylmethoxy)-biphenyl-4-ylmethyl]-nicotinamide; and    8-Cyclopentyl-6-ethyl-3-thiophen-2-yl-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacene,    or the pharmaceutically acceptable salts and/or isomers, tautomers, solvates, polymorphs, isotopic variations or metabolites, enantiomeres or mixtures of enantiomeres thereof.    
     
     
         6 ) The pharmaceutical compositions according to  claim 1 , wherein the weight ratios of the active substance 1 to the active substance 2 are in the range from about 1:100 to about 100:1.  
     
     
         7 ) The pharmaceutical composition according to  claim 1 , wherein a single administration corresponds to a dose of the active substance 1 and 2 of 0.01 to 10000 μg.  
     
     
         8 ) The pharmaceutical composition according to  claim 1 , which is in the form of a formulation suitable for inhalation.  
     
     
         9 ) The pharmaceutical composition according to  claim 8 , wherein the formulation is selected from a group consisting of inhalable powders, propellant-containing metering aerosols and propellant-free inhalable solutions or suspensions.  
     
     
         10 ) The pharmaceutical composition according to  claim 9 , which is in the form of an inhalable powder which contains the active substances 1 and 2 in admixture with suitable physiologically acceptable excipients selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients with one another.  
     
     
         11 ) The pharmaceutical composition according to  claim 9 , which is in the form of an inhalable powder which contains only the active substances 1 and 2 as its ingredients.  
     
     
         12 ) The pharmaceutical composition according to  claim 9 , which is the form of a propellant-containing inhalable aerosol which contains the active substances 1 and 2 in dissolved or dispersed form.  
     
     
         13 ) The pharmaceutical composition according to  claim 12 , wherein the composition comprises, as propellant gas, hydrocarbons selected from n-propane, n-butane or isobutane or halohydrocarbons selected from chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.  
     
     
         14 ) The pharmaceutical composition according to  claim 13 , wherein the propellant gas is TG134a, TG227 or a mixture thereof.  
     
     
         15 ) The pharmaceutical composition according to  claim 9 , which is in the form of a propellant-free inhalable solution or suspension which contains water, ethanol or a mixture of water and ethanol as solvent.  
     
     
         16 ) The pharmaceutical composition according to  claim 15 , wherein the pH is 2-7.  
     
     
         17 ) A method of treating inflammatory or obstructive diseases of the respiratory tract comprising administering to a patient in need thereof a pharmaceutically effective amount of a composition according to  claim 1.